Development of a novel stereo-selective synthetic route towards Pumiliotoxin C, potent neurotoxin, via asymmetric Diels-Alder and sequential protonation-nucleophilic addition as key reaction steps Open Access

Mwenda, Edward (2012)

Permanent URL: https://etd.library.emory.edu/concern/etds/jd472x116?locale=en
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Abstract

The study towards the synthesis of the naturally occurring (-)-pumiliotoxin C of the
dendrobatid alkaloid has been outlined. The bicyclic skeleton of the pumiliotoxin C was be
rapidly assembled in one key reaction step using a novel regio- and enantiocontrolled
asymmetric [4+2] cycloaddition of TpMo(CO)2(3-alkenyl-η3-4,5,6-pyridinyl) diene 39. Diene 39
was formed from the TpMo(CO)2(η3-5-oxo-pyridinyl) scaffold 27 via a Grignard reaction and
dehydration reaction. This was later followed by sequential protonation-nucleophilic addition as
key reaction step for the introduction of the alkyl side chain.

Table of Contents

Table of Contents:

1. Introduction…………………………………………………………………………………..12
2. Results and Discussion…………..…………………………………………………………..25
3. Conclusion…………………………………………………………………………………...38
4. Experimentals………………………………………………………………………………..40

List of Schemes:

Scheme 1: Total synthesis of (-)-pumiliotoxin C by Oppolzer……………………………….….13
Scheme 2: Total synthesis of (-)-pumiliotoxin C by Comins…………………………………….14
Scheme 3: Total synthesis of (-)-pumiliotoxin C by Feringa………………………….…………15
Scheme 4: Total synthesis of (-)-pumiliotoxin C by Overman..…………………………………16
Scheme 5: Total synthesis of (-)-pumiliotoxin C by Back…...……..…………….……………...17
Scheme 6: [4 + 2] cycloaddition of diene 30…………………….…..…………………………..21
Scheme 7: [4 + 2] cycloaddition/demetallation sequence provides 2,6-cis tetrahydrochromes....22
Scheme 8: Retrosynthetic analysis……………………………….…..…………………………..23
Scheme 9: Summary of results achieved by Shuangpei Liu….….…..…………………………..24
Scheme 10: Proposed modification of (±)-pumiliotoxin C...…….…..…………………………..24
Scheme 11: Preperation of Cbz-protected Molybdenum Scaffold (±)-27…..….………………..25
Scheme 12: Synthesis of Tricholomalides B…..….……………………………………………..26
Scheme 13: Formation of diene (±)-39…..….………………………………………..…...……..28
Scheme 14: Dienophiles explored for the [4 + 2] cycloaddition……..……..….………………..28
Scheme 15: [4 + 2] cycloaddition of with phenyl vinyl sulphone.…..…………………………..29
Scheme 16: Lewis acid promoted [4 + 2] cycloaddition of (±)-39…..…..………..……………..30
Scheme 17: Proposed mechanism for cycloaddition of (±)-39...…….…..……………..………..30
Scheme 18: Consecutive Diels-Alder-Decarbonylation reaction………………………………..33
Scheme 19: Protonation-Nucleophilic addition reaction……….………………………………..35
Scheme 20: Complementary demetallation protocols………….………………………………..38
Scheme 21: Summary of the progress made……………………………………………………39

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